Ethanol withdrawal-induced depressive symptoms in animals and therapeutic potential of sigma 1 receptor ligands

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1 Pharmacological Reports 2013, 65, ISSN Copyright 2013 by Institute of Pharmacology Polish Academy of Sciences Review Ethanol withdrawal-induced depressive symptoms in animals and therapeutic potential of sigma 1 receptor ligands Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL Kraków, Poland Correspondence:, skuza@if-pan.krakow.pl Abstract Clinical evidence has indicated a high degree of comorbidity of alcoholism and depression. Manifestation of the depression symptoms during abstinence increases the likelihood of relapse and indicates a worse prognosis in terms of treatment outcome. The depressive symptoms may be alcohol independent or alcohol induced. In this paper, only the ethanol-related depression is the focus of interest. In preclinical studies, some models of depressive-like symptoms induced by chronic alcohol treatment and withdrawal were proposed. In this minireview, the results concerning the depression-like behavior and some accompanying biochemical changes induced by prolonged ethanol exposure and its cessation in rats and mice were summarized. Moreover, the therapeutic potential of sigma 1 receptor ligands for the treatment of depression disorder induced by ethanol abuse and withdrawal is discussed. Key words: ethanol abuse, depression, comorbidity, animal models, drugs treatment, sigma 1 ligands Introduction A significant comorbid expression of alcoholism and affective disorders (major depression, dysthymia) has been shown by clinical evidences [e.g, 3, 13, 23]. Alcohol dependence and abuse is one of the most costly health problems in the world from both a social and an economic point of view. Comorbidity of depression in alcoholism implies a worse prognosis as to treatment outcome. The treatment becomes more complex because these patients have more physical, psychological, familial and social problems than alcoholics without comorbid depression. The causal relationship between alcoholism and depression has not yet been fully understood. In many alcohol dependent subjects, depression is a reactive response to chronic alcohol use and withdrawal, potentially exerting a significant influence on treatment prospects and increasing the likelihood of relapse [13, 15]. Alcohol withdrawal and depression-like symptoms in animals The depression-like symptoms induced by chronic ethanol consumption and its withdrawal have been investigated in some preclinical studies. They were carried out on rats or mice, chronically treated with ethanol and subjected to very diverse procedures in detail (ethanol concentration, time and way of treatment, duration of abstinence, etc.). Regardless of the differ- Pharmacological Reports, 2013, 65,

2 ences, this research brought many interesting results at the behavioral and biochemical levels, which should be helpful in understanding of the mechanism of disturbances in these disorders. Detection of depression-related behaviors in a mouse model based on a 6-week free-choice ethanol (10%, v/v) consumption followed by 2-week abstinence was reported by Pang et al. [33]. Mice withdrawn from alcohol showed an increased immobility time in the forced swim test (FST), reduced saccharin consumption and increased latency to feed in the novelty-suppressed feeding test. Thus, mice revealed depressiverelated symptoms. By comparison, there was no significant effect of alcohol withdrawal on anxietyrelated behaviors as determined by the light-dark box test and the elevated plus maze test. Interestingly, the access to running-wheels throughout the duration of abstinence in alcohol-dependent mice attenuated the depressive-like behavior observed in the above mentioned tests. In conclusion, given the link between ethanol withdrawal and depression, the proposed model seems to be useful for the study of the pathophysiology underlying alcohol-related depression. Moreover, some clinical data support the observations that exercises produced a protective effect on ethanol withdrawal-related depression [51]. The clinical and experimental data indicated that ethanol-induced depressive-like behavior was associated with alterations in corticotropin releasing factor (CRF) and neuropeptide Y (NPY) systems in the brain. The experiments of Walker et al. [54] evaluated behavior of adult Wistar rats in the FST and subsequently the levels of brain neuropeptides following long-term ethanol exposure. Performance in the FST was assessed in rats during acute withdrawal and protracted abstinence following a two-week intermittent ethanol vapor exposure period. In addition, because of known NPY and CRF involvement in depressive-like behaviors, their levels were measured in selected brain regions (amygdala, frontal cortex, hippocampus, hypothalamus) of the ethanol vapor- and airexposed animals following the final protracted withdrawal test. As previously suggested, the increased expression of CRF and a reduced expression of NPY played an essential role in the pathogenesis of depression and anxiety. On the contrary, one of the common mechanisms of action of antidepressant and anxiolytic drugs is a decrease in CRF and an increase in NPY expression [e.g., 29, 34]. The data demonstrated by Walker et al. [54] indicated that NPY and CRF were associated with the reduction [39, 53] and induction [18, 31], respectively, of the depressive- and anxietylike behavior in preclinical models. Furthermore, the data have suggested that alterations in NPY and CRF systems in response to chronic alcohol exposure could contribute to intensified ethanol intake. It is widely known that prenatal ethanol exposure leads to a number neurochemical and behavioral dysfunctions and, in consequences, to depressive disorders in adult life. The mechanism that links prenatal alcohol exposure and depression has not been fully elucidated, yet. In the studies of Caldwell et al. [5], female C57BL/6J mice and a voluntary two bottle choice paradigm for prenatal alcohol exposure were applied. The learned helplessness procedure and the FST were used for assessing the depressive-like behavior. Moreover, the brain-derived neurotrophic factor (BDNF) protein and mrna levels were determined in the medial frontal cortex and hippocampal formation. The prenatally ethanol-exposed mice displayed an increased learned helplessness behavior as well as immobility in the FST in comparison to control mice. Importantly, prenatally ethanol-exposed mice and control (saccharin) mice did not differ in the locomotor activity test. The behavioral changes correlated with the reduced basal BDNF protein levels in the medial frontal cortex but not in the hippocampal formation of ethanol-exposed mice, while total mrna and BDNF transcripts (containing exon III, I or VI) were reduced in both medial frontal cortex and hippocampus. The studies of Caldwell et al. [5] showed that prenatally ethanol-exposed female mice displayed depressive-like behavior when tested as adults (female offspring). Females were chosen for the mentioned studies due to the clinical observation that depression symptoms have been observed significantly more frequently in women than in men [e.g. 14]. According to neurotrophic hypothesis of depression [9], BDNF plays a key role in the pathogenesis of this disease and in the mechanism of antidepressant efficacy of clinically active drugs [2, 28, 45]. Another possibility is that the changes in BDNF protein and mrna levels may be secondary to the changes in serotonin neurotransmission which, as previously shown, is disturbed by chronic treatment with ethanol [58, 59]. The discovery of neurogenesis in the adult hippocampus has became the basis for the neuronal plasticity hypothesis of depression, proposed by Duman and coworkers [6 8, 24, 25]. According to this concept, 1682 Pharmacological Reports, 2013, 65,

3 Ethanol withdrawal-related depression and sigma 1 receptor ligands the disturbances in the adult neurogenesis seem to play an essential role in the pathogenesis of depression [6, 7, 9, 25]. Factors that reduced neurogenesis, like stress or dysregulations of monoamines have been shown to increase the depressive-like behavior in animals, while antidepressant treatments reversed it [19, 21, 24, 38]. Neurogenesis declines until it ceases in the young adult mammalian brain with two exceptions: the olfactory bulb and the hippocampus produce new neurons throughout adult life. In the subgranular cell layer of the dentate gyrus, hippocampal progenitors proliferate and migrate a short distance into the granule cell layer, where they differentiate into hippocampal granule cells. Multiple factors seem to regulate adult neurogenesis (hormones, neurotransmitters, trophic factors). Different possible functions and effects of neurogenesis have been considered. The exact function of newborn cells in the adult brain is not known, though many studies implicate hippocampal neurogenesis in functions related to the hippocampus, such as learning, memory and mood [25]. Stress, glucocorticoids, age, opiates and binge ethanol consumption have been shown to decrease cell proliferation and neurogenesis [40]. Interestingly, continuous ethanol consumption was reported to cause no significant change in cell proliferation. Stevenson et al. [52] proposed the experimental model in which the depressive-like behavior in mice, induced by self-administration of ethanol, was correlated with the reduction in hippocampal neurogenesis. Male C57BL/6J mice were allowed to voluntarily drink ethanol (10%v/v) in their home cage for 28 days. One or 14 days after alcohol withdrawal mice were tested in the FST. After 14 days (but not on 1 day) of abstinence from alcohol drinking, the depression-like behavior (prolonged the immobility time) was observed in mice. The significant increase in depression-like symptoms was associated with a reduction in proliferating cell nuclear antigen and doublecortin immunoreactivity in the dentate gyrus of the hippocampus indicating that both the number of proliferating neural progenitor cells and immature neurons was reduced. Chronic treatment with desipramine, classical antidepressant drug, during 14-day abstinence period, counteracted both depressant-like behavior and the reduction in hippocampal neurogenesis [52]. Moreover, this study supported the idea that depression-like behavior during abstinence may be functionally linked to abstinence-induced neuroadaptative changes. Such conclusion was confirmed also by the results of Briones and Woods [4] who demonstrated that changes in neurogenesis and BDNF expression in the rat brain are a possible mechanism involved in the depression-like effects during the abstinence period after chronic binge pattern alcohol use. Male Sprague- Dawley rats were trained to self-administer ethanol in a binge-like pattern for 12 days. Two days after the last drinking session, rats were tested in the sucrose preference test to evaluate anhedonia and in the open field test after habituation to evaluate behavioral despair. Chronic binge drinking resulted in the development of a depressive phenotype, decreased survival and differentiation of neural progenitor cells in the hippocampus and decreased BDNF level during the withdrawal period. The most important finding is that augmenting BDNF actions through the use of tyrosine kinase B (a BDNF receptor) agonist restored neurogenesis and abolished the alcohol-induced anhedonia and despair behaviors, seen during the abstinence period. These results suggest that BDNF might be a molecule that can be targeted for interventions in alcoholism-depression co-incidence. The role of NMDA receptors in alcohol withdrawal-induced depression The key role of the glutamate system, especially N- methyl-d-aspartate (NMDA) receptors, was accepted both in the mechanism of antidepressant activity and in the neuropathological changes induced by chronic ethanol exposure. Prolonged ethanol treatment and withdrawal induces neuroadaptations at the cellular and subcellular levels in the brain which can lead to prolonged and permanent changes especially in NMDA receptor subunit level and composition [41]. The chronic ethanol exposure induces an upregulation of NMDA receptor subunits (NR1, NR2A, NR2B) in the central nucleus of amygdala and to changes in synaptic transmission via glutamatergic synapses [41]. The potential antidepressant-like activity of NMDA receptor antagonists was first demonstrated by Skolnick group in the 1990s and up to now a multitude of literature data have been accumulated [22, 42, 46, 47, 56]. Recent studies of Yilmaz et al. [57] demonstrated that chronic treatment with antidepressant drugs also modified the NMDA receptor subunits. The effects of Pharmacological Reports, 2013, 65,

4 the treatment with venlafaxine or escitalopram on the expression of NR2B subunit of NMDA receptors in the rat hippocampus were studied. After induction of depression (chronic mild stress and sucrose preference test), a decrease in the concentration of NR2B was observed. Venlafaxine, but not escitalopram, corrected the reduced NR2B level, thus, it had a protective effect on NMDA receptors. Some studies have demonstrated that antidepressants treatment reduces depressive symptoms in alcohol-dependent subjects but it has not been found to be helpful in reducing excessive drinking in these patients. Only a limited number of well-controlled clinical studies on the efficacy of antidepressant use for alcoholics have been published [30]. On the other hand, some controversies were elicited by clinical observations that antidepressants could worsen the prognosis of alcoholism in the subjects with the comorbidity of depression and alcoholism. Such a possibility was confirmed by studies of Alen et al. [1]. In this study fluoxetine or venlafaxine were given to rats for 15 days and their effects on ethanol deprivation and subsequent alcohol consumption were evaluated. Initially, fluoxetine reduced alcohol deprivation effect and venlafaxine did not affect it. However, in the consecutive days, both antidepressants increased alcohol consumption. In summary, antidepressant treatment may increase alcohol consumption in rats after a period of alcohol deprivation and this could be related to alterations in the reward circuitry. Some clinical trials demonstrated that in patients with co-occurring depression and alcohol dependence the combined treatments with: sertraline and naltrexone [37] or escitalopram and memantine (MEM) [27] were more effective than separate drug treatments in individuals with co-occurrence of both disorders. From the point of view of this paper, two compounds seem to be very interesting, amantadine (AMA) and MEM, which are both uncompetitive NMDA receptor antagonists, currently used in clinical practice. AMA is applied as an antiparkinsonian drug and tested in the depression disorders [55]. MEM is clinically used in mild to moderate Alzheimer s disease, and tested in depression, bipolar disorder, generalized anxiety disorder, opioid and alcohol dependence [10, 36]. It is noteworthy that both AMA and MEM exhibit a marked affinity for sigma 1 receptor (Ki = 7.4 nm and 2.6 nm, respectively) [48]. Sigma ligands as potential therapeutic agents in ethanol withdrawal-related depression The selective sigma 1 receptor agonists induced antidepressant-like activity in many experimental paradigms, e.g. FST, tail suspension test, olfactory bulbectomy model, conditioned fear stress [see: 11, 50]. Taking into consideration that sigma 1 receptor ligands are able to modify the activity of many neurotransmitter systems in the brain, including glutamate/nmda, serotonergic, monoaminergic (noradrenergic) pathways, as well as some other signaling routes (e.g. neurotrophin and growth factor signaling paths), essential for the antidepressant activity, their recognition as antidepressant drugs has been growing.. According to recent studies by Fujimoto et al. [12], the selective sigma 1 receptor agonist, SA4503 (cutamesine), was shown to increase BDNF expression in the hippocampus of rats. Chronic treatment of rat B104 neuroblastoma cells with cutamesine caused a time- and dose-dependent potentiation of the BDNF secretion without affecting the BDNF mrna level. Cutamesine decreased the intracellular level of pro- BDNF and mature BDNF whereas increased the extracellular level of mature BDNF. The pulse-chase experiment indicated that the knockdown of Sig-1Rs decreased the secreted mature BDNF in B104 cells without affecting the synthesis of BDNF. These findings indicate that the sigma 1 receptor agonist cutamesine potentiates the post-translational processing of neurotrophins. In contrast, clinically used antidepressants promote the transcriptional upregulation of BDNF. Though the role of sigma receptors in the behavioral, toxic, and addictive effects of cocaine and methamphetamine remains the best studied, sigma receptors have also been implicated in the addictive potential of ethanol. The motivational effects of alcohol intake are also believed to involve sigma receptors, for instance, pretreatment with the functional sigma receptor antagonist BD1047 was shown to dosedependently block ethanol-induced conditioned place preference (CPP) [26]. In contrast, the putative sigma receptor agonist, PRE-084 [20] enhanced ethanol CPP in a dose-dependent manner [26]. In Sardinian alcohol-preferring rats, with the genetic predisposition to alcoholism, the sigma 1 antagonist NE-100 as 1684 Pharmacological Reports, 2013, 65,

5 Ethanol withdrawal-related depression and sigma 1 receptor ligands well as BD-1063 dose-dependently reduced ethanol intake [44, 45]. Previous studies indicated that the antidepressantlike activity of many antidepressant drugs and also sigma 1 receptor agonists may be enhanced by their co-administration in combination with an uncompetitive NMDA receptor antagonists, e.g., AMA, MEM or neramexane [22, 42, 49]. It is noteworthy that AMA behaved as a sigma 1 receptor ligand in the rat forebrain homogenates. In NG neuroblastoma cells, it potentiated the bradykinin-induced mobilization of intracellular Ca 2+, mimicking the effect of sigma 1 receptor agonists [35, 48]. These positive modulations show the bell-shaped concentrationresponse curve usually observed with sigma 1 receptor agonists [16]. In our studies, the potential role of sigma 1 receptors in the depression-like behavior induced by self-administration of alcohol and withdrawal was estimated in male C57BL/6J mice. Mice were allowed to self-administer ethanol (in raising concentrations of 4%, 8% and 10% v/v) for 16 days. Then alcohol was withdrawn for 14 days (abstinence period). Desipramine, a classical tricyclic antidepressant, and other drugs (fluvoxamine, sertraline and MEM) were given during the abstinence period. The results showed that abstinence from voluntary alcohol drinking led to an increase depression-like behavior in ethanol drinking mice as estimated by the FST and tail suspension test. Fluvoxamine and sertraline, the SSRIs with a relatively high affinity for sigma 1 receptors, as well as MEM, did not modify depression-like behavior in ethanol drinking mice. However, fluvoxamine given jointly with MEM normalized the immobility time in the FST, similarly as desipramine. In contrast, co-treatment with sertraline and MEM, did not induce such an activity [50]. The results did not conclusively clarify the role of sigma 1 receptors in depression-like symptoms in mice during abstinence. The significance of those findings requires further clarification, especially because the data concerning this problem are rather sparse. Summing up, in the treatment of depression induced by ethanol withdrawal, the choice of proper antidepressant is of great importance. As indicated in this paper, the changes in neurogenesis, BDNF expression in the brain, especially in the hippocampal formation, and in the NMDA receptor function play the key role in the pathogenesis of depression and in the disturbances induced by ethanol withdrawal. Taking into consideration the unique mechanism of action of sigma 1 receptor ligands and the results obtained so far, their role as potential therapeutic agents in ethanol-related depression seems to be promising but requires extensive further studies. The NMDA receptor antagonists, showing the antidepressant-like activity in animals as well as in clinical trials (AMA, MEM, ketamine), administered in combination with the sigma 1 receptor agonists, may be future option in the treatment of depression in alcohol withdrawal syndrome. Acknowledgments: This work was supported by grant POIG /09-00 from European Regional Development Fund. References: 1. Alén F, Orio L, Gorriti MÁ, de Heras RG, Ramírez- López MT, Pozo MÁ, de Fonseca FR: Increased alcohol consumption in rats after subchronic antidepressant treatment. Int J Neuropsychopharmacol, 2013, 8, Altar CA, Whitehead RE, Chen R, Wörtwein G, Madsen TM: Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain. Biol Psychiatry, 2003, 54, Brière FN, Rohde P, Seeley JR, Klein D, Lewinsohn PM: Comorbidity between major depression and alcohol use disorder from adolescence to adulthood. Compr Psychiatry, 2013, [Epub ahead of print]. 4. Briones TL, Woods J: Chronic binge-like alcohol consumption in adolescence causes depression-like symptoms possibly mediated by the effects of BDNF on neurogenesis. Neuroscience, 2013, 254, Caldwell KK, Sheema S, Paz RD, Samudio-Ruiz SL, Laughlin MH, Spence NE, Roehlk MJ et al.: evidence for reductions in the levels of brain-derived neurotrophic factor in a mouse model. Pharmacol Biochem Behav, 2008, 90, Duman RS, Heninger GR, Nestler EJ: A molecular and cellular theory of depression. Arch Gen Psychiatry, 1997, 54, Duman RS, Malberg J, Nakagawa S, D Sa C: Neuronal plasticity and survival in mood disorders. Biol Psychiatry, 2000, 48, Duman RS, Malberg J, Thome J: Neural plasticity to stress and antidepressant treatment. Biol Psychiatry, 1999, 46, Duman RS, Monteggia LM: A neurotrophic model for stress-related mood disorders. Biol Psychiatry, 2006, 59, Evans SM, Levin FR, Brooks DJ, Garawi F: A pilot double-blind treatment trial of memantine for alcohol dependence. Alcohol Clin Exp Res, 2007, 31, Pharmacological Reports, 2013, 65,

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